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Arthur I. Cederbaum - One of the best experts on this subject based on the ideXlab platform.
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hbx inhibits CYP2E1 gene expression via downregulating hnf4α in human hepatoma cells
PLOS ONE, 2014Co-Authors: Hongming Liu, Arthur I. Cederbaum, Guiyu Lou, Xiaodong Wang, Lixia Gan, Bin XieAbstract:CYP2E1, one of the cytochrome P450 mixed-function oxidases located predominantly in liver, plays a key role in metabolism of xenobiotics including ethanol and procarcinogens. Recently, down-expression of CYP2E1 was found in hepatocellular carcinoma (HCC) with the majority to be chronic hepatitis B virus (HBV) carriers. In this study, we tested a hypothesis that HBx may inhibit CYP2E1 gene expression via hepatocyte nuclear factor 4α (HNF4α). By enforced HBx gene expression in cultured HepG2 cells, we determined the effect of HBx on CYP2E1 mRNA and protein expression. With a bioinformatics analysis, we found a consensus HNF-4α binding sequence located on −318 to −294 bp upstream of human CYP2E1 promoter. Using reporter gene assay and site-directed mutagenesis, we have shown that mutation of this site dramatically decreased CYP2E1 promoter activity. By silencing endogenous HNF-4α, we have further validated knockdown of HNF-4α significantly decreased CYP2E1expression. Ectopic overexpression of HBx in HepG2 cells inhibits HNF-4α expression, and HNF-4α levels were inversely correlated with viral proteins both in HBV-infected HepG2215 cells and as well as HBV positive HCC liver tissues. Moreover, the HBx-induced CYP2E1 reduction could be rescued by ectopic supplement of HNF4α protein expression. Furthermore, human hepatoma cells C34, which do not express CYP2E1, shows enhanced cell growth rate compared to E47, which constitutively expresses CYP2E1. In addition, the significantly altered liver proteins in CYP2E1 knockout mice were detected with proteomics analysis. Together, HBx inhibits human CYP2E1 gene expression via downregulating HNF4α which contributes to promotion of human hepatoma cell growth. The elucidation of a HBx-HNF4α-CYP2E1 pathway provides novel insight into the molecular mechanism underlining chronic HBV infection associated hepatocarcinogenesis.
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Nrf2 and antioxidant defense against CYP2E1 toxicity.
Sub-cellular biochemistry, 2013Co-Authors: Arthur I. CederbaumAbstract:The transcription factor Nrf2 regulates the expression of important cytoprotective enzymes. Induction of cytochrome P450 2E1(CYP2E1) is one of the central pathways by which ethanol generates oxidative stress. CYP2E1 can be induced by ethanol and several low molecular weight chemicals such as pyrazole. The chapter discusses biochemical and toxicological effects of CYP2E1 and the effects of Nrf2 in modulating these actions of CYP2E1.Besides ethanol, CYP2E1 metabolizes and activates many other important toxicological compounds. One approach to try to understand basic effects and actions of CYP2E1 was to establish HepG2 cell lines that constitutively express human CYP2E1. Ethanol, polyunsaturated fatty acids and iron were toxic to the HepG2 cells which express CYP2E1 (E47 cells) but not control C34HepG2 cells which do not express CYP2E1.Toxicity was associated with enhanced oxidant stress and could be prevented by antioxidants and potentiated if glutathione (GSH) was removed. The E47 cells had higher GSH levels and a Twofold increase in catalase, cytosolic and microsomal glutathione transferase, and heme oxygenase-1 (HO-1) than control HepG2 cells due to activation of their respective genes. These activations were prevented by antioxidants, suggesting that reactive oxygen species (ROS) generated by CYP2E1 were responsible for the up-regulation of these antioxidant genes. This upregulation of antioxidant genes may reflect an adaptive mechanism to remove CYP2E1-derived oxidants. Increases in Nrf2 protein and mRNA were observed in livers of chronic alcohol-fed mice or rats and of pyrazole-treated rats or mice, conditions known to elevate CYP2E1. E47 cells showed increased Nrf2 mRNA and protein expression compared with control HepG2 C34 cells. Upregulation of antioxidant genes in E47 cells is dependent on Nrf2 and is prevented by siRNA-Nrf2. Blocking Nrf2 by siRNA-Nrf2 decreases GSH and increases ROS and lipid peroxidation, resulting in decreased mitochondrial membrane potential and loss of cell viability of E47 cells but not C34 cells. Nrf2 is activated and levels of Nrf2 protein and mRNA are increased when CYP2E1 is elevated. These results suggest that Nrf2 plays a key role in the adaptive response against increased oxidative stress caused by CYP2E1 in the HepG2 cells.
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Ethanol Induction of CYP2A5: Role of CYP2E1-ROS-Nrf2 Pathway
Toxicological sciences : an official journal of the Society of Toxicology, 2012Co-Authors: Xu Hannah Zhang, Arthur I. CederbaumAbstract:Chronic ethanol consumption was previously shown to induce CYP2A5 in mice, and this induction of CYP2A5 by ethanol was CYP2E1 dependent. In this study, the mechanisms of CYP2E1-dependent ethanol induction of CYP2A5 were investigated. CYP2E1 was induced by chronic ethanol consumption to the same degree in wild-type (WT) mice and CYP2A5 knockout (Cyp2a5 –/–) mice, suggesting that unlike the CYP2E1-dependent ethanol induction of CYP2A5, ethanol induction of CYP2E1 is not CYP2A5 dependent. Microsomal ethanol oxidation was about 25% lower in Cyp2a5 –/– mice compared with that in WT mice, suggesting that CYP2A5 can oxidize ethanol although to a lesser extent than CYP2E1 does. CYP2A5 was induced by short-term ethanol consumption in human CYP2E1 transgenic knockin (CYP2E1 –/– KI) mice but not in CYP2E1 knockout (CYP2E1 –/–) mice. The redox-sensitive transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) was also induced by acute ethanol in CYP2E1 –/– KI mice but not in CYP2E1 –/– mice. Ethanol induction of CYP2A5 in Nrf2 knockout (Nrf2 –/–) mice was lower compared with that in WT mice, whereas CYP2E1 induction by ethanol was comparable in WT and Nrf2 –/– mice. Antioxidants (N-acetyl-cysteine and vitamin C), which blocked oxidative stress induced by chronic ethanol in WT mice and acute ethanol in CYP2E1 –/– KI mice, also blunted the induction of CYP2A5 and Nrf2 by ethanol but not the induction of CYP2E1 by ethanol. These results suggest that oxidative stress induced by ethanol via induction of CYP2E1 upregulates Nrf2 activity, which in turn regulates ethanol induction of CYP2A5. Results obtained from primary hepatocytes, mice gavaged with binge ethanol or fed chronic ethanol, show that Nrf2-regulated ethanol induction of CYP2A5 protects against ethanol-induced steatosis.
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CYP2E1 potentiates toxicity in obesity and after chronic ethanol treatment.
Drug metabolism and drug interactions, 2012Co-Authors: Arthur I. CederbaumAbstract:CYP2E1 activates several hepatotoxins and contributes to alcoholic liver damage. In this report, we review our studies on whether induction of CYP2E1 can potentiate liver injury in obesity. Acetone- or pyrazole-induced severe liver injury in obese mice as compared to obese controls and lean mice. Severe liver injury was associated with elevated oxidative and nitrosative stress and could be blunted by inhibitors of CYP2E1 and inducible nitric oxide synthase (iNOS). S-Adenosyl-L-methionine (SAM) lowered the elevated oxidative and nitrosative stress, steatosis, liver injury and mitochondrial dysfunction in the pyrazole-treated obese mice. The protection by SAM may have therapeutic applications against metabolic complications caused by obesity. The role of CYP2E1 in chronic ethanol-induced liver injury was studied using wild-type (WT) mice, CYP2E1 knockout (KO) mice and humanized CYP2E1 knockin (KI) mice. Ethanol produced fatty liver and oxidant stress in WT mice; these effects were blunted in the CYP2E1 KO mice but restored in the CYP2E1 KI mice. Significant liver injury was produced in the ethanol-fed KI mice in association with elevated oxidant stress and levels of human CYP2E1. Collectively, these studies show that CYP2E1 contributes to ethanol-induced and obesity-induced oxidant stress and liver injury.
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Ethanol Induction of CYP2A5: Permissive Role for CYP2E1
Drug metabolism and disposition: the biological fate of chemicals, 2010Co-Authors: Jian Zhuge, Arthur I. CederbaumAbstract:CYP2A5 metabolizes xenobiotics and activates hepatocarcinogens, and induction occurs in response to hepatic damage and cellular stress. We evaluated whether ethanol can elevate CYP2A5 and whether CYP2E1 plays a role in the ethanol induction of CYP2A5. Wild-type (WT), CYP2E1 knockout (KO), and CYP2E1 knockin (KI) mice were fed ethanol for 3 weeks. Ethanol increased CYP2E1 and CYP2A5 protein and activity in WT mice but not in the KO mice. Induction of CYP2A5 (and CYP2E1) was restored in the KI mice. Ethanol induction of CYP2A5 occurred only after CYP2E1 was first induced. Immunohistochemical staining revealed that CYP2E1 and CYP2A5 colocalize to the same zones in the liver. Ethanol also elevated CYP2A5 mRNA levels in WT and KI mice but not in KO mice. Induction of CYP2A5 by cadmium was partially decreased in KO mice compared with WT or KI mice. Ethanol elevated CYP2A4 mRNA levels in all mice although the extent of induction was lowest in the KO mice. In summary, ethanol elevated mouse hepatic CYP2A5 levels, which may be of toxicological significance because CYP2A5 metabolizes nicotine and other drugs and activates hepatocarcinogens. Induction of CYP2A5 by ethanol is potentiated by the induction of CYP2E1. We speculate that ethanol induction of CYP2E1 followed by increases in reactive oxygen species and activation of Nrf2 are important steps in the mechanism by which ethanol induces CYP2A5. The possibility that induction of CYP2E1 is permissive for the induction of CYP2A5 may reflect a new contribution by CYP2E1 to the actions of ethanol.
Frank J. Gonzalez - One of the best experts on this subject based on the ideXlab platform.
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human placental lactogen induces CYP2E1 expression via pi 3 kinase pathway in female human hepatocytes
Drug Metabolism and Disposition, 2014Co-Authors: Jin Kyung Lee, Frank J. Gonzalez, Hye Jin Chung, Liam Fischer, James H Fischer, Hyunyoung JeongAbstract:The state of pregnancy is known to alter hepatic drug metabolism. Hormones that rise during pregnancy are potentially responsible for the changes. Here we report the effects of prolactin (PRL), placental lactogen (PL), and growth hormone variant (GH-v) on expression of major hepatic cytochromes P450 expression and a potential molecular mechanism underlying CYP2E1 induction by PL. In female human hepatocytes, PRL and GH-v showed either no effect or small and variable effects on mRNA expression of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5. On the other hand, PL increased expression level of CYP2E1 mRNA with corresponding increases in CYP2E1 protein and activity levels. Results from hepatocytes and HepaRG cells indicate that PL does not affect the expression or activity of HNF1α, the known transcriptional activator of basal CYP2E1 expression. Furthermore, transient transfection studies and Western blot results showed that STAT signaling, the previously known mediator of PL actions in certain tissues, does not play a role in CYP2E1 induction by PL. A chemical inhibitor of PI3-kinase signaling significantly repressed the CYP2E1 induction by PL in human hepatocytes, suggesting involvement of PI3-kinase pathway in CYP2E1 regulation by PL. CYP2E1-humanized mice did not exhibit enhanced CYP2E1 expression during pregnancy, potentially because of interspecies differences in PL physiology. Taken together, these results indicate that PL induces CYP2E1 expression via PI3-kinase pathway in human hepatocytes.
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Identification of 2-Piperidone as a Biomarker of CYP2E1 Activity Through Metabolomic Phenotyping
Toxicological sciences : an official journal of the Society of Toxicology, 2013Co-Authors: Jie Cheng, Chi Chen, Krausz W. Kristopher, Soumen K. Manna, Mike Scerba, Fred K. Friedman, Hans Luecke, Jeffrey R. Idle, Frank J. GonzalezAbstract:Cytochrome P450 2E1 (CYP2E1) is a key enzyme in the metabolic activation of many low molecular weight toxicants and also an important contributor to oxidative stress. A noninvasive method to monitor CYP2E1 activity in vivo would be of great value for studying the role of CYP2E1 in chemical-induced toxicities and stress-related diseases. In this study, a mass spectrometry-based metabolomic approach was used to identify a metabolite biomarker of CYP2E1 through comparing the urine metabolomes of wild-type (WT), CYP2E1-null, and CYP2E1-humanized mice. Metabolomic analysis with multivariate models of urine metabolites revealed a clear separation of CYP2E1-null mice from WT and CYP2E1-humanized mice in the multivariate models of urine metabolomes. Subsequently, 2-piperidone was identified as a urinary metabolite that inversely correlated to the CYP2E1 activity in the three mouse lines. Backcrossing of WT and CYP2E1-null mice, together with targeted analysis of 2-piperidone in mouse serum, confirmed the genotype dependency of 2-piperidone. The accumulation of 2-piperidone in the CYP2E1-null mice was mainly caused by the changes in the biosynthesis and degradation of 2-piperidone because compared with the WT mice, the conversion of cadaverine to 2-piperidone was higher, whereas the metabolism of 2-piperidone to 6-hydroxy-2-piperidone was lower in the CYP2E1-null mice. Overall, untargeted metabolomic analysis identified a correlation between 2-piperidone concentrations in urine and the expression and activity of CYP2E1, thus providing a noninvasive metabolite biomarker that can be potentially used in to monitor CYP2E1 activity.
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sex steroid hormones regulate constitutive expression of CYP2E1 in female mouse liver
American Journal of Physiology-endocrinology and Metabolism, 2013Co-Authors: Maria Konstandi, Jie Cheng, Frank J. GonzalezAbstract:CYP2E1 is of paramount toxicological significance because it metabolically activates a large number of low-molecular-weight toxicants and carcinogens. In this context, factors that interfere with CYP2E1 regulation may critically affect xenobiotic toxicity and carcinogenicity. The aim of this study was to investigate the role of female steroid hormones in the regulation of CYP2E1, as estrogens and progesterone are the bases of contraceptives and hormonal replacement therapy in menopausal women. Interestingly, a fluctuation in the hepatic expression pattern of CYP2E1 was revealed in the different phases of the estrous cycle of female mice, with higher CYP2E1 expression at estrus (E) and lower at methestrus (ME), highly correlated with that in plasma gonadal hormone levels. Depletion of sex steroids by ovariectomy repressed CYP2E1 expression to levels similar to those detected in males and cyclic females at ME. Hormonal supplementation brought CYP2E1 expression back to levels detected at E. The role of progesterone appeared to be more prominent than that of 17β-estradiol. Progesterone-induced CYP2E1 upregulation could be attributed to inactivation of the insulin/PI3K/Akt/FOXO1 signaling pathway. Tamoxifen, an anti-estrogen, repressed CYP2E1 expression potentially via activation of the PI3K/Akt/FOXO1 and GH/STAT5b-linked pathways. The sex steroid hormone-related changes in hepatic CYP2E1 expression were highly correlated with those observed in Hnf-1α, β-catenin, and Srebp-1c. In conclusion, female steroid hormones are clearly involved in the regulation of CYP2E1, thus affecting the metabolism of a plethora of toxicants and carcinogenic agents, conditions that may trigger several pathologies or exacerbate the outcomes of various pathophysiological states.
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Role of CYP2E1 in Diethylnitrosamine-Induced Hepatocarcinogenesis In vivo
Cancer research, 2007Co-Authors: Jin Seok Kang, Frank J. Gonzalez, Hideki Wanibuchi, Keiichirou Morimura, Shoji FukushimaAbstract:CYP2E1 metabolizes many low-molecular weight toxins and carcinogens. Some in vitro experiments suggest that CYP2E1 may be involved in the metabolic activation of diethylnitrosamine. However, there has been no direct evidence demonstrating a role for CYP2E1 in diethylnitrosamine-mediated carcinogenesis in vivo. To clarify this, we carried out a diethylnitrosamine-induced hepatocarcinogenesis experiment using CYP2E1-null mice. Male 14-day-old wild-type and CYP2E1-null mice were treated with diethylnitrosamine (10 mg/kg of body weight) and killed at weeks 24 and 36 after diethylnitrosamine treatment for investigation of tumors and at 6, 24, and 48 h for examination of apoptosis and gene expression. Liver weights of CYP2E1-null mice were significantly different at weeks 24 and 36 compared with wild-type mice (P < 0.01). Liver tumor incidences of CYP2E1-null mice were significantly decreased at weeks 24 and 36 compared with wild-type mice (P < 0.01). CYP2E1-null mice showed significant decrease in the multiplicities of hepatocellular adenoma at weeks 24 and 36 (P < 0.05 and P < 0.01, respectively), and of hepatocellular carcinoma at week 36 (P < 0.01) compared with wild-type mice. Apoptotic index and caspase-3 and/or Bax mRNA expression of CYP2E1-null mice were significantly different at 6, 24, and 48 h after diethylnitrosamine treatment compared with wild-type mice (P < 0.05). We conclude that CYP2E1-null mice show lower tumor incidence and multiplicity compared with wild-type mice in diethylnitrosamine-induced hepatocarcinogenesis. It is suggested that CYP2E1 completely participates in diethylnitrosamine-induced hepatocarcinogenesis, and high frequency of tumors in wild-type mice could be associated with the increased apoptosis.
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cytochrome p450 CYP2E1 but not nicotinamide adenine dinucleotide phosphate oxidase is required for ethanol induced oxidative dna damage in rodent liver
Hepatology, 2005Co-Authors: Blair U Bradford, Hiroshi Kono, Fuyumi Isayama, Oksana Kosyk, Michael D Wheeler, Taro E Akiyama, Lisa Bleye, Kristopher W Krausz, Frank J. GonzalezAbstract:The occurrence of malignant tumors of the upper gastrointestinal tract and liver is, based largely on epidemiological evidence, causally related to the consumption of ethanol. It is widely recognized that oxidants play a key role in alcohol-induced liver injury; however, it is unclear how oxidants may be involved in DNA damage. We asked whether nicotinamide adenine dinucleotide phosphate oxidase, cytochrome P450 CYP2E1, or both are responsible for the production of DNA damage. The rodent Tsukamoto-French model of intragastric ethanol infusion was used. Wistar rats, CYP2E1-, p47phox-null, and hCYP2E1 transgenic mice were used. The abundance of oxidative DNA adducts, mutagenic apurinic/apyrimidinic sites, and expression of base excision DNA repair genes was determined. In rats and wild-type mice, ethanol treatment for 4 weeks led to an increase in oxidative DNA damage and induction of expression of the base excision DNA repair genes that are known to remove oxidative DNA lesions. No increase in either of the endpoints was observed in ethanol-treated CYP2E1-null mice, whereas the magnitude of response in p47phox-null mice and transgenic hCYP2E1 was identical to that in wild types. The increase in expression of DNA repair genes was completely abolished by treatment with the P450 inhibitor 1-aminobenzotriazole. In conclusion, the data support the hypothesis that oxidative stress to DNA is induced in liver by ethanol. Furthermore, although it was shown that nicotinamide adenine dinucleotide phosphate oxidase-derived oxidants are critical for the development of ethanol-induced liver injury, CYP2E1 is required for the induction of oxidative stress to DNA, and thus may play a key role in ethanol-associated hepatocarcinogenesis. (HEPATOLOGY 2005;41:336–344.)
Laurence S Kaminsky - One of the best experts on this subject based on the ideXlab platform.
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human extrahepatic cytochromes p450 function in xenobiotic metabolism and tissue selective chemical toxicity in the respiratory and gastrointestinal tracts
Annual Review of Pharmacology and Toxicology, 2003Co-Authors: Xinxin Ding, Laurence S KaminskyAbstract:Cytochrome P450 (CYP) enzymes in extrahepatic tissues often play a dominant role in target tissue metabolic activation of xenobiotic compounds. They may also determine drug efficacy and influence the tissue burden of foreign chemicals or bioavailability of therapeutic agents. This review focuses on xenobiotic-metabolizing CYPs of the human respiratory and gastrointestinal tracts, including the lung, trachea, nasal respiratory and olfactory mucosa, esophagus, stomach, small intestine, and colon. Many CYPs are expressed in one or more of these organs, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2S1, CYP3A4, CYP3A5, and CYP4B1. Of particular interest are the preferential expression of certain CYPs in the respiratory tract and the regional differences in CYP expression profile in different parts of the gastrointestinal tract. Current research activities on the characterization of CYP expression, function, and regulation in the...
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human extrahepatic cytochromes p450 function in xenobiotic metabolism and tissue selective chemical toxicity in the respiratory and gastrointestinal tracts
Annual Review of Pharmacology and Toxicology, 2003Co-Authors: Xinxin Ding, Laurence S KaminskyAbstract:Cytochrome P450 (CYP) enzymes in extrahepatic tissues often play a dominant role in target tissue metabolic activation of xenobiotic compounds. They may also determine drug efficacy and influence the tissue burden of foreign chemicals or bioavailability of therapeutic agents. This review focuses on xenobiotic-metabolizing CYPs of the human respiratory and gastrointestinal tracts, including the lung, trachea, nasal respiratory and olfactory mucosa, esophagus, stomach, small intestine, and colon. Many CYPs are expressed in one or more of these organs, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2S1, CYP3A4, CYP3A5, and CYP4B1. Of particular interest are the preferential expression of certain CYPs in the respiratory tract and the regional differences in CYP expression profile in different parts of the gastrointestinal tract. Current research activities on the characterization of CYP expression, function, and regulation in these tissues, as well as future research needs, are discussed.
Susanna S.t. Lee - One of the best experts on this subject based on the ideXlab platform.
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resistance to carbon tetrachloride induced hepatotoxicity in mice which lack CYP2E1 expression
Toxicology and Applied Pharmacology, 1998Co-Authors: Felice W Y Wong, W Y Chan, Susanna S.t. LeeAbstract:CYP2E1 knockout mice (CYP2E1-/-) were used to investigate the involvement of CYP2E1 in the development of carbon tetrachloride (CCl4)-induced hepatotoxicity. Male CYP2E1-/- and wild-type (CYP2E1+/+) mice were given a single i.p. injection of 1 ml/kg (= 1.59 g/kg) CCl4 and 24 h later liver injury was assessed by elevations of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and histopathology. No significant increases in serum ALT and AST activities were observed in CYP2E1-/- mice when compared to wild-type counterparts after CCl4 exposure. No detectable abnormality in liver histology was found in CYP2E1-/- mice after CCl4 exposure. In contrast, CCl4 treatment resulted in 442- and 125-fold increases in serum ALT and AST activities, respectively, in wild-type mice. Consistent with the results of serum ALT and AST activities, severe hepatic damage was noted in livers of wild-type mice, indicating the importance of CYP2E1 in mediating the hepatic damage following CCl4 exposure in these mice. In addition, a dramatic decrease in CYP2E1-catalyzed p-nitrophenol activity and complete loss of immunoreactive CYP2E1 were observed in wild-type mice after CCl4 treatment, suggesting that CYP2E1 was degraded during the process of CCl4-induced hepatotoxicity. These studies conclusively demonstrate that CYP2E1 is the major factor involved in the CCl4-induced hepatotoxicity in mice.
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Role of CYP2E1 in the Hepatotoxicity of Acetaminophen
The Journal of biological chemistry, 1996Co-Authors: Susanna S.t. Lee, Jeroen T. M. Buters, Thierry Pineau, Pedro M. Fernandez-salguero, Frank J. GonzalezAbstract:CYP2El, a cytochrome P-450 that is well conserved across mammalian species, metabolizes ethanol and many low molecular weight toxins and cancer suspect agents. The CYP2E1 gene was isolated, and a mouse line that lacks expression of CYP2E1 was generated by homologous recombination in embryonic stem cells. Animals deficient in expression of the enzyme were fertile, developed normally, and exhibited no obvious phenotypic abnormalities, thus indicating that CYP2E1 has no critical role in mammalian development and physiology in the absence of external stimuli. When cyp2el knockout mice were challenged with the common analgesic acetaminophen, they were found to be considerably less sensitive to its hepatotoxic effects than wild-type animals, indicating that this P-450 is the principal enzyme responsible for the metabolic conversion of the drug to its active hepatotoxic metabolite.
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Reduction of benzene metabolism and toxicity in mice that lack CYP2E1 expression
Toxicology and applied pharmacology, 1996Co-Authors: John L. Valentine, Susanna S.t. Lee, Frank J. Gonzalez, Mark J. Seaton, Bahman Asgharian, Georgia M. Farris, J. Christopher Corton, Michele A. MedinskyAbstract:Abstract Transgenic CYP2E1 knockout mice ( CYP2E1 -/- ) were used toinvestigate the involvement of CYP2E1 in the in vivo metabolism of benzene and in the development of benzene-induced toxicity. After benzene exposure, absence of CYP2E1 protein was confirmed by Western blot analysis of mouse liver samples. For the metabolism studies, male CYP2E1 -/- and wild-type control mice were exposed to 200 ppm benzene, along with a radiolabeled tracer dose of [ 14 C]benzene (1.0 Ci/mol) by nose-only inhalation for 6 hr. Total urinary radioactivity and all radiolabeled individual metabolites were reduced in urine of CYP2E1 -/- mice compared to wild-type controls during the 48-hr period after benzene exposure. In addition, a significantly greater percentage of total urinary radioactivity could be accounted for as phenylsulfate conjugates in CYP2E1 -/- mice compared to wild-type mice, indicating the importance of CYP2E1 in oxidation of phenol following benzene exposure in normal mice. For the toxicity studies, male CYP2E1 -/- wild-type, and B6C3F1 mice were exposed by whole-body inhalation to 0 ppm (control) or 200 ppm benzene, 6 hr/day for 5 days. On Day 5, blood, bone marrow, thymus, and spleen were removed for evaluation of micronuclei frequencies and tissue cellularities. No benzene-induced cytotoxicity or genotoxicity was observed in CYP2E1 -/- mice. In contrast, benzene exposure resulted in severe genotoxicity and. cytotoxicity in both wild-type and B6C3F1 mice. These studies conclusively demonstrate that CYP2E1 is the major determinant of in vivo benzene metabolism and benzene-induced myelotoxicity in mice.
Hye Gwang Jeong - One of the best experts on this subject based on the ideXlab platform.
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saponins isolated from the root of platycodon grandiflorum protect against acute ethanol induced hepatotoxicity in mice
Food and Chemical Toxicology, 2009Co-Authors: Tilak Khanal, Jae Ho Choi, Yong Pil Hwang, Young Chul Chung, Hye Gwang JeongAbstract:Abstract The protective effects of saponins isolated from the root of Platycodon grandiflorum (Changkil saponins: CKS) against alcoholic steatosis in liver injury induced by acute ethanol administration were investigated. Pretreatment with CKS prior to ethanol administration significantly prevented the increases in serum alanine aminotransferase activity, hepatic TNF-α level, hepatic lipid peroxidation and hepatic triglyceride level. CKS prevented ethanol-induced steatosis and necrosis, as indicated by liver histopathological studies. Additionally, CKS protected against ethanol-induced depletion of hepatic glutathione levels. CYP2E1 has been suggested as a major contributor to ethanol-induced oxidative stress and liver injury. The concurrent administration of CKS efficaciously abrogated the CYP2E1 induction and CYP2E1-dependents hydroxylation of aniline as compared to the individual treatment at higher doses. These findings suggest that CKS may prevent ethanol-induced acute liver injury, possibly through its ability to block CYP2El-mediated ethanol bioactivation and its free radical scavenging effects.
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protective effect of saponins derived from the roots of platycodon grandiflorum against carbon tetrachloride induced hepatotoxicity in mice
Food and Chemical Toxicology, 2008Co-Authors: Kyungjin Lee, Jae Ho Choi, Yong Pil Hwang, Young Chul Chung, Hyung Gyun Kim, Eun Hee Han, Young Chun Lee, Hye Gwang JeongAbstract:The purpose of this study was to investigate the protective effects of the saponins isolated from the root of Platycodi Radix (Changkil saponins: CKS) on carbon tetrachloride (CCl4)-induced hepatotoxicities in mice. Pretreatment with CKS prior to the administration of CCl4 significantly prevented the increase in serum alanine aminotransferase and aspartate aminotransferase activities and hepatic lipid peroxidation formation. In addition, CKS prevented CCl4-induced apoptosis and necrosis, as indicated by a liver histopathologic study and DNA laddering. To determine whether Fas/Fas ligand (FasL) pathway involved in CCl4-induced acute liver injury, Fas and FasL proteins and caspase-3, -8 activities were tested by western blotting and ELISA. CKS markedly decreased CCl4-induced Fas/FasL protein expression levels and in turn attenuated CCl4-induced caspase-3, -8 activities in mouse livers. Additionally, CKS protected the CCl4-induced depletion of hepatic glutathione levels. The effect of CKS on CYP2E1, the major isozyme involved in CCl4 bioactivation, was investigated. Treatment with CKS resulted in a significant decrease in the CYP2E1-dependent hydroxylation of aniline. In addition, CKS exhibited antioxidant effects on FeCl2-ascorbate induced lipid peroxidation in liver homogenates, and on superoxide radical scavenging activity. These findings suggest that the protective effects of CKS against CCl4-induced acute liver injury possibly involve mechanisms related to its ability to block CYP2El-mediated CCl4 bioactivation and its free radical scavenging effects, and that is also protects against Fas/FasL pathway mediated apoptosis.
